Directing ricin-based immunotoxins with targeting affibodies and KDEL signal peptide to cancer cells effectively induces apoptosis and tumor suppression

Autor: Seong Guk Park, Heeyeon Kim, Heejin Jun, Sun Young Choi, Eunhee Kim, Sebyung Kang
Jazyk: angličtina
Rok vydání: 2022
Předmět:
Zdroj: Journal of Nanobiotechnology, Vol 20, Iss 1, Pp 1-17 (2022)
Druh dokumentu: article
ISSN: 1477-3155
DOI: 10.1186/s12951-022-01601-8
Popis: Abstract The plant toxin ricin, especially its cytotoxic A chain (RTA), can be genetically engineered with targeting ligands to develop specific anti-cancer recombinant immunotoxins (RITs). Here, we used affibody molecules targeting two cancer biomarkers, the receptors HER2 and EGFR, along with the KDEL signal peptide to construct two cancer-specific ricin-based RITs, HER2Afb-RTA-KDEL and EGFRAfb-RTA-KDEL. The affibodies successfully provided target-specificity and subsequent receptor-mediated endocytosis and the KDEL signal peptide routed the RITs through the retrograde transport pathway, effectively delivering RTA to the cytosol as well as avoiding the alternate recycling pathway that typical cancer cells frequently have. The in vivo efficacy of RITs was enhanced by introducing the albumin binding domain (AlBD) to construct AlBD/HER2Afb/RTA-KDEL. Systemic administration of AlBD-containing RITs to tumor-bearing mice significantly suppressed tumor growth without any noticeable side-effects. Collectively, combining target-selective affibody molecules, a cytotoxic RTA, and an intracellularly designating peptide, we successfully developed cancer-specific and efficacious ricin-based RITs. This approach can be applied to develop novel protein-based “magic bullets” to effectively suppress tumors that are resistant to conventional anti-cancer drugs. Graphical Abstract
Databáze: Directory of Open Access Journals
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